Abnormal protein tyrosine phosphatase (PTPase) activity has been reported to be associated with age, diabetes and also with certain cancers. We have been studying the regulation of insulin receptor and epidermal growth factor receptor functions by employing different PTPase inhibitors. Newly synthesized arylphosphonates effectively inhibited dephosphorylation of prelabeled receptors by particulate PTPases and recombinant PTP-1B. Also, peptides containing two variations of the phosphotyrosyl ester moieties have been synthesized and tested for their effect on PTPase activity. These variations were the phosphonomethyl-L- phenylalanine (pmp) and phosphonodifluoromethyl-L-phenylalanine (F2pmp). It has been found that a F2pmp-containing peptide potently inhibited dephosphorylation of insulin receptor by PTP-1B.